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Jumping into the game
September 2010
by David Hutton  |  Email the author
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JUPITER, Fla.—A new player in drug discovery is teaming up with a familiar name to identify new drugs for Parkinson's disease (PD) that have greater efficacy and safety compared to current therapies.

Envoy Therapeutics Inc., a recently formed drug discovery company, recently announced that it has begun a research collaboration with the Scripps Research Institute to identify new drugs for PD. Using funding provided by Envoy, scientists at the two organizations will apply Scripps high-throughput screening (HTS) capabilities to discover compounds that modulate a target protein discovered by Envoy.

"The parties are jointly developing and evaluating various assays in order to optimize the efficiency and effectiveness of the screening," says Dr. Stephen Hitchcock, senior vice president of drug discovery at Envoy. "Subsequent to initial screening, the parties will identify a subset of hits which will be the focus of additional validation and optimization studies."

According to Scott Forrest, director of business and technology development at the Scripps Research Institute, what makes Envoy Therapeutics an attractive partner for this collaboration is a combination of excellent science, aggressive pursuit of novel targets (as a small biotech, Envoy can quickly push into "fresh" target space more rapidly than Big Pharma) and a multidisciplinary approach to drug discovery that combines strong biology with HTS and medicinal chemistry.  

"Any time you can bring those three things together, you position yourself to be on the forefront of drug discovery, which is quite simply the goal of Scripps Florida," he says.
For its part, Scripps Florida brings to the collaboration access to state-of-the-art HTS/uHTS facilities and an assay formatting/HTS team with both a strong industry background and a diverse cross-section of expertise.  

"That's the mix we are shooting for within our HTS group, as we believe it allows for flexible thinking and troubleshooting while retaining a project execution mindset, as well as data packages that can plug right in to commercial development efforts," Forrest says.
And there is ample market for new treatments.

PD affects more than a million people in the United States. The main symptoms include muscle rigidity, tremor and a slowing of physical movement. These symptoms are caused by the progressive loss of a subset of dopamine-producing neurons within the basal ganglia, a brain region involved in controlling movement.

"Collaborating with biopharmaceutical pioneers like Envoy is critical to our translating scientific discoveries into new medicines," adds Dr. Patrick Griffin, director of translational research and chairman of the Department of Molecular Therapeutics at Scripps. "We are pleased to be joining Envoy in the fight against this devastating disease."

The most widely prescribed medicine today for Parkinson's patients is L-DOPA, a drug that releases dopamine to compensate for the decline in naturally produced dopamine. However, patients taking L-DOPA experience a gradual loss of efficacy and a number of side effects, including involuntary movements. These side effects are thought to be caused by a lack of specificity of L-DOPA's action, resulting in effects on multiple cell types within the brain.

Hitchcock says his company's focus in the collaboration is on the discovery and development of a daily, orally available alternative to L-DOPA. He adds that the intermingling of many different cell types within brain regions makes identifying targets that modulate specific pathways very challenging.

Using its proprietary bacTRAP technology, Envoy's scientists have identified a protein that is selectively expressed in a specific cell type within the striatum, an area of the basal ganglia deep inside the brain that plays an important role in planning and modulating movement. They believe that modulating this protein with a small-molecule drug will more precisely affect specific brain cells, achieving the efficacy of L-DOPA without the side effects.

"Envoy's bacTRAP technology overcomes this problem by allowing for the expression of potential drug target proteins to be compared across multiple co-localized cell types," Hitchcock says. "In this case, all the potential drug targets in D2 neurons in the striatum have been compared across D1 and many other neuron-types. This approach has revealed a novel target, highly enriched in D2 expressing striatal neurons."

Hitchcock says Envoy's technology takes advantage of the way cells make proteins.

"A cell first creates a messenger RNA copy of a gene. Next, the cell sends this messenger RNA out of the nucleus to the protein-making parts of the cells, the ribosomes," he explains. "The ribosomes then read the genetic sequence of the mRNA and put amino acids together into a chain that becomes a protein. Envoy's technology cleverly isolates the mRNA being read by the ribosomes in one type of cell without also isolating the mRNA from any other cell types. In other words, we isolate RNA where proteins are being made."

Additionally, Hitchcock says the approach utilizes several distinct technologies.
 
"First is homologous recombination to insert large pieces of DNA known as bacterial artificial chromosomes, or BACs, into cells," he says. "Second is the creation of transgenic mice that possess these BACs and that we can use to study one specific cell type."

The mice in each colony have a specially engineered, tagged protein that exists only in the ribosomes of the cell type to be studied.

"This tag enables us, using affinity purification, to isolate all of the mRNA being read by the ribosomes of the one type of cells while ignoring all other types of cells," Hitchcock says. "Finally, through the use of existing genetic analysis platforms such as sequencers and microarrays, we're able to identify all of the genes that are expressed in one specific cell type and then quantitatively measure how much mRNA and protein are made from that gene in that cell type. Previous approaches have relied, unsuccessfully, on attempts to isolate cells of one cell type from all of the other cell types."

Hitchcock says Envoy's proprietary technology is far more precise, isolating the mRNA in one specific cell type without needing to isolate and stress the cells, which changes the expression of many proteins. The result can help ensure the development of drugs with greater efficacy and fewer side effects.

According to Hitchcock, undesirable side effects with CNS-targeted therapeutics are common and often originate from the promiscuous nature of biological targets that are engaged by current drugs.

"Many neurological disorders are defined by deficiencies in specific populations of neurons and neuronal circuitry," he says. "However the intermingling of many different cell types within brain regions makes identifying targets that modulate specific pathways very challenging."

The tremendous difficulties in precision targeting of therapeutics can be illustrated in Parkinson's disease and schizophrenia where dysfunctions in specific dopaminergic pathways are features of both conditions.

Hitchcock points out that in Parkinson's disease, L-DOPA provides remarkable efficacy by activating a subset of dopamine D2 receptor expressing neurons in the striatum.

"However, detrimental side effects originating from activation of other closely-related members of the dopamine receptor family within the striatum, as well as many other brain regions, limits the utility of L-DOPA," he explains. "Current antipsychotic drugs used to treat schizophrenia possess complex pharmacology but exhibit the common feature of antagonizing D2 receptors. Since D2 receptors are expressed on neurons in multiple pathways, mechanism-related side-effects including tardive dyskinesia and hyperprolactinemia are common."

An alternative to engaging broadly expressed biological targets is to identify and modulate targets that are specific to a given circuit that is known to be disrupted in disease, which Hitchcock says is in bacTRAP's sweet spot—the capability to precisely measure the expression of potential drug target proteins, by cell type.

"This is enormously powerful when dealing with diseases of the brain where efforts to date have been largely unsuccessful as a result of multiple co-localized cell types," he says.

As a result, Hitchcock says Envoy's assay development and HTS activities with Scripps will form the foundation upon which subsequent hit-to-lead and lead optimization activities will eventually settle upon a lead compound for preclinical testing.

"We will enter that critical stage with the invaluable knowledge that we are modulating a highly selective target, thereby increasing the likelihood of success at the preclinical and subsequent clinical trial stages," he says.

 
Code: E091020

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